Inflammation Introduction 2025 PDF

INFLAMMATION INFLAMMATION LAB #1 1. General features of inflammation 2. Acute inflammation Stimuli for inflammation Stages Outcomes of acute inflammation 3. Chronic inflammation Causes and morphologic features of chronic inflammation...

INFLAMMATION INFLAMMATION LAB #1 1. General features of inflammation 2. Acute inflammation Stimuli for inflammation Stages Outcomes of acute inflammation 3. Chronic inflammation Causes and morphologic features of chronic inflammation 4. Local and systemic effects of inflammation 5. Consequences of defective or excessive inflammation 6. Repair responses after injury and inflammation 7. Mediators of inflammation INFLAMMATION LAB LEARNING OBJECTIVES After completing this lab, you should be able to: State the purpose of inflammation Name the key chemical mediators involved in inflammation and outline their roles Describe the vascular and cellular phases of acute inflammation Define an exudate and differentiate between the types Compare and contrast acute and chronic inflammation Outline the consequences of chronic inflammation Describe the processes of healing and repair Compare and contrast first and second intention healing State the key factors that can impede the healing process DOI: (10.1152/ajpheart.00148.2019)  INJURY INFLAMMATIO N The Inflammatory Response to Injury The initial inflammatory response is vascular Chemical signals mediate the inflammatory process Cellular reaction follows vascular reaction Leukocytes are the cells of inflammation Inflammation has effects beyond the site of injury Acute inflammation follows brief injury Chronic inflammation occurs with persistent injury INFLAMMATION Inflammation Medical Animation CHEMICAL MEDIATORS INFLAMMATION (inflammatio) Inflammation is a protective response of human body against local tissue damage (damaging agents) INFLAMMATION (inflammatio) Without inflammation, infections would go unchecked, and wounds would never heal Inflammation Inflammation – is the physiologic body reaction in response to injury The body tries to protect itself from harmful pathogens and physical or chemical irritants Inflammation Inflammatory Response  Can be acute or chronic Cells of Inflammation Chemicals of Inflammation vascular first, then cellular Granulocytes  Cell-Derived Vascular response  arteriolar vasoconstriction neutrophils, basophils, Plasma-Derived followed by vasodilation eosinophils Hyperemia – capillaries Agranulocytes  flooded with blood, causes monocytes, edema lymphocytes Edema – plasma leaks into tissues Platelets (hemostasis) Cellular response Cells leave blood via diapedesis  Cells involved in inflammation Robbins and Cotran Pathologic Basis of Disease – Kumar, Abbas, Aster, W.B. Saunders, 9th, 2015 Robbins and Cotran Pathologic Basis of Disease – Kumar, Abbas, Aster, W.B. Saunders, 9th, 2015  TISSUE INJURY Immediate vascular changes Influx of inflammatory cells Widespread effects of inflammatory mediators Repair of damaged tissue INFLAMMATION (inflammatio) Consists of two main vessel-tissues components: 1. Violation of microcirculation with exudation Vascular response 2. Emigration of leukocytes and proliferation Cellular response  The response, which serves to control and eliminate altered cells, microorganisms, (1) the vascular phase, and (2) the cellular phase, which twoleads to the migration which leadsantigens, occurs to an increase in in phases: of leukocytes from the blood flow and changes in the circulation and their INFLAMMAT small blood vessels of the microcirculation activation to eliminate the injurious agent ION (inflammati o) The primary function of inflammatory response is to limit the injurious effect of the pathologic agent and remove the injured tissue components, thereby allowing tissue repair to take place  INFLAMMATION (inflammatio) Inflammatory conditions are named by adding the suffix -itis to the affected organ or system: Appendicitis – refers to inflammation of the appendix Pericarditis – inflammation of the pericardium Neuritis – inflammation of a nerve Not a synonym for infection!  General Components of the inflammatory process include white blood cells (WBC) and plasma proteins features – Normally present in the blood – They need to be brought to the site of infection and/or of tissue damage Non-specific inflammat Induced by chemical mediators produced by damaged host cells ion  Develops in alive tissue process  Inflammation is a process, which is: dynamic (steps of inflammation) complex (activation/inhibition) tightly regulated (mediators of inflammation) Also, a potentially harmful process – Components of inflammation can also injury normal tissue – Inappropriate inflammatory response may lead to autoimmunity Goals of inflammation To eliminate the initial cause of tissue injury Diluting, destroying and neutralizing the harmful agents To remove the damaged tissue To initiate the process of repair  Systems involved in the inflammatory response Immune system Endocrine system Nervous system Circulatory system Blood Connective tissue  Stimuli for inflammation EXOGENOUS INFLAMMATION ENDOGENOU S (external) (internal)  Stimuli for inflammation The causes of inflammation are many and varied: Exogenous causes: Physical agents: Mechanic agents: fractures, foreign corps, sand Thermal agents: burns, freezing Chemical agents: toxic gases, acids, bases Biological agents: bacteria, viruses, parasites Endogenous causes: [factors, which arise in organism, as the result of any other diseases] Circulation disorders: thrombosis, infarction, hemorrhage, hypoxia Enzyme's activation: acute pancreatitis Metabolic products deposals: uric acid, urea BIOLOGICAL CHEMICAL PHYSICAL  VASCULAR IMMUNOLOGICAL ENDOGENO ENDOGENOUS TOXINS US CAUSES NEOPLASIA METABOLIC 1) VASCULAR CAUSES (hemodynamic) Hypertension Ischemia Blood clot Obstruction Infarct Vasoconstiction Endothelial damage Atherosclerosis 2) IMMUNOLOGICAL CAUSES Ab Ab AUTOAGRESSION Ag Autoantibodies Ab Anti-TPO Anti-Tg Anti-GBM Immunological complexes DNA 3) ENDOGENOUS „TOXINS”  Bilirubin → Jaundice  Uremic toxins → Uremia  Uric acid → Gout  Hydrochloric acid → Peptic ulcer disease → Barrett's esophagus → Aspiration pneumonia  Bile → Acute pancreatitis 4) NEOPLASIA 5) METABOLIC CAUSES Hypoxia Hyperlipidemia Hyperglycemia Hyperhomocysteinemia Oxidation stress The risk factors of cardiovascular diseases Body response to injury Local response Inflammation Systemic (whole body) response Acute-phase reaction EFFECTS / SIGNS OF INFLAMMATION LOCAL SYSTEMIC Local signs of inflammation ERYTHEMA, REDNESS (rubor) Celsus HEAT (calor) 53 p.n.e.-7 n.e. EDEMA, SWELLING (tumor) Galen PAIN (dolor) 129-200 n.e. LOSS OF FUNCTION (functio  Calor Rubor Tumor Dolor Functio laesa Heat due Erythema Swelling Pain Loss of to due to due to function increased increased increased blood blood flow vascular flow and dilated permeabilit vessels 1minute 2 y 5 10 minutes minutes minutes  Local signs Physiology Causes of inflammation Redness Arises from increased blood flow and Hyperemia from (rubor) accumulation at the point of injury or vasodilatation inflammation Heat (color) Due to accumulation of warm flow of Increased metabolism at blood and the heat produced from local inflammatory site reaction/ irritation Swelling Released inflammatory mediators at the Fluid shift to interstitial (tumor) site lead to increased fluid extravasation spaces Fluid exudates accumulation Pain (dolor) Mediated by cytokines like bradykinins Change in pH and prostaglandins Change in ionic concentration Nerve stimulation by chemicals (histamine, prostaglandins) Pressure form fluid exudates  Local signs Physiology Causes of inflammation Redness (rubor) Vasodilation Histamine Increased blood flow NO, PGE2 Heat (color) Vasodilation Histamine, serotonin Swelling (tumor) Vasodilation Histamine, serotonin Extravasion of fluid (permeability) C3a, C5a Cellular influx (chemotaxis) Bradykinin Leukotrienes (C4, D4, E4) PAF Substance P Pain (dolor) Release of soluble mediators PGE2 Extravasion of fluid (permeability) Bradykinin Cellular influx (chemotaxis) TNF, IL-1 Chemokines C3a, C5a Leukotriene B4 Loss of function Elevated cellular metabolism Lysosomal enzymes of leukocytes (functio laesa) ROS, NO  SEROTONIN PGE2 LTB4 KININS PAIN HISTAMINE H+, K+ MECHANICAL PRESSURE HYPOXIA....... K+......... K+ K+ K+.... K+ K+ ATP H+ H+ H+ H+ H+ H + H+ H+ H+ PAIN H+ H+  FEVER [production of endogenous pyrogens (IL-1 and IL- 6, TNF-α, INF) by neutrophils and macrophages] Systemic LEUKOCYTOSIS INCREASED ESR [erythrocyte sedimentation rate] signs of ACUTE-PHASE REACTION [С-reactive protein, ceruloplasmine, γ-globulins] inflammati LYMPHOID HYPERPLASIA on [increase in the peripheral blood of juvenile and stab neutrophils] Systemic inflammatory response syndrome (SIRS) → in severe cases Represents responses to cytokines produced either by bacterial products or by other inflammatory stimuli Fever as a general sign of inflammation Pyroge ns (LPS from bacteria) Macrophages IL-1 and Perivascular TNF-α cells of the hypothalam  us cyclooxygenase activity  PGE2  temperature set point  Clinical Manifestations of Inflammation Fever triggers Beneficial aspects of An increase in pulse The onset of fever is activation of the body’s fever include: and respiration follows triggered by the defense mechanisms the rise in metabolism release of cytokines as a result of an increased killing of increase in body The most potent of these microorganisms temperature cytokines are IL-1, IL- 6, and TNF- increased phagocytes by α (released from mononuclear neutrophils phagocytic cells)  these cytokines cause fever by their increased proliferation of T cells ability to initiate metabolic enhanced the activity of changes in the temperature interferon regulating center  The synthesis of prostaglandin E2 (PGE2) is the most critical metabolic change PGE2 acts directly to increase the Clinical thermostatic set point Manifestati The hypothalamus then activates the sympathetic branch of the autonomic ons of nervous system to stimulate: increased muscle tone and shivering Inflammati decreased perspiration and blood flow to on the periphery Epinephrine released from the adrenal medulla increases the metabolic rate With the physiologic thermostat fixed at a higher-than-normal temperature, the rate of heat production is increased until the body temperature reaches the new set point Clinical Manifestations of Inflammation As the set point is raised, the hypothalamus signals and increases in heat production and conservation to raise the body temperature to the new level At this point the individual feels chilled and shivers The shivering response is the body’s method of raising the body’s temperature until the new set point is attained This seeming paradox is dramatic: the body is hot yet an individual piles on blankets and may go to bed to go warm When the circulating body temperature reaches the set point of the core body temperature, the chills and warmth- seeking behavior cease  PYROGENS → substances that stimulate prostaglandin synthesis in the hypothalamus EXOGENOUS ENDOGENOUS Bacterial IL-1 endotoxins (LPS) TNF-α Lipid A IL-6 INF-γ  Stages of the fever Def. Increase in body Exogenous pyrogen (bacteria) temperature with efficient mechanisms of thermoregulation Endogenous pyrogen (macrophages) Occurs when increased PGE2 ! temperature is produced in response Accumulation of Na+ to pyrogens Changing the setting center of thermoregulation Stimulation of the reception center and heat production FEVER PGE2 NSAIDs  CLASSIFICATION OF FEVER Feverishness 39 ºC Hyperpyrexia >41.0 ºC Processes associated with fever Feverish tachycardia [increased heartbeat rate] Tachypnea [increased respiratory rate] Increased water loss through the skin and 0.5-1.0 L/ 1ºC respiratory system CNS dysfunction: Bad mood Hallucinations Disturbances of consciousness Seizures  Laboratory symptoms of inflammation results from the increased Increased release of leukocytes form the leukocytosis bone marrow Change in the an increase in the circulating number percentage of of one or more types of leukocytes leukocytes (blood smear) may be found Presence of young results from the increased release of forms of leukocytes leukocytes form the bone marrow  INCREASED LEUKOCYTOSIS Normal value: LEUKOCYTES = 3500 - 10000/µL NORMAL BLOOD SMEAR Neutrophils 50-70% Eosinophils 0-1% Basophils 2-4% Lymphocytes 25-40% Monocytes 2-8% https://www.youtube.com/watch?v=cI9GO bT73lY Blood smear Hyperleukocytosis - Bacterial infections neutrophils - Myocardial infarction, hemorrhage Eosinophilia - Atopy - Parasitic infections - Collagenases Lymphocytosis - Viral infections Monocytosis - Recovery period - Endocarditis Neutropenia - Sepsis Lymphopenia - Systemic lupus erythematosus (SLE) - Glucocorticoids therapy (GCs) Mediators responsible for changes in leukocytosis G-CSF GM-CSF IL-1 IL-6 IL-3 Erythrocyte sedimentation rate (ESR) Normal value after 1h: Women – up to 12 mm Men – up to 8 mm high RBCs sedimentation rate (via fibrinogen) Erythrocyte sedimentation rate (ESR) Increased concentration in plasma: γ-globulin α-globulin fibrinogen Decreased concentration: albumin Erythrocyte sedimentation rate (ESR) Inflammation Tissue necrosis Cancer „three-digit” ESR Hodgin’s lymphoma Acute-phase reaction Part of the innate immunity Includes the earliest changes occurring in response to tissue damage It manifests in increase of protein production --- acute-phase proteins 25 % Acute-phase proteins concentration 25 Acute-phase proteins POSITIVE C-reactive protein! (CRP) NEGATIVE Serum amyloid A (SAA) Procalcytonin (PTC) Cerruloplasmin Haptoglobin Albumin α-1 antitrypsin Transferrin α-1 antichymotrypsin  Acute-phase IL-6 TNF-α INF-γ MACROPHAGES Acute- phase proteins C-reactive protein (CRP) Source: Liver Wall of arteries Especially changed by atherosclerosis [Increased CRP is a predictor of cardiovascular events] CRP concentration in acute-phase may increase up to 1000-fold Sensitive marker of inflammation, tissue damage and necrosis correlates with the activity and dynamic of the inflammatory process Function of CRP: Similar to immunoglobulin (Ig)G, it activates complement, binds to Fc receptors and acts as an opsonin for various pathogens Procalcitonin (PCT) Calcitonin precursor Source: [NO!!! C-cells of the thyroid] Macrophages of the liver Leukocytes Neuroendocrine cells of the lungs and intestines Marker of severe infection or sepsis LYMPHOID HYPERPLASIA Lymphatic System Lymphangitis (inflammation of lymph vessels) Lymphadenitis (infected lymph nodes) Lymphadenopathy (lymph node enlargement) Reactive hyperplasia (non-infected enlargement)  Types of inflammation ACUTE CHRONIC inflammation: inflammation: Early onset Later onset (seconds to minutes) (days) Short duration Longer duration (minutes to days) (weeks to years) Involving fluid Involving lymphocytes exudation (edema) and macrophages, and with blood vessel polymorphonuclear cell proliferation and (neutrophils) fibrosis (scarring) emigration Types of inflammation Granulomatous inflammation: Distinctive pattern of chronic inflammation Activated macrophages (epithelioid cells) predominate +/- Multinucleated giant cells Sequence of Events in Acute Inflammation Outcomes of acute inflammation Process has one of three general outcomes: I. Complete resolution II. Healing by connective tissue replacement (fibrosis, scar) III. Progress to chronic inflammation Acute inflammation will be affected by: the nature and intensity of injury the tissue involved the host responsiveness Sequence of Events in Acute Inflammation Classification of the inflammation I. Based on the time of duration II. Based on the reactivity of organism III. Based on the predominant component  Classification of the inflammation I. Based on the time of duration: Acute inflammation (inflammatio acuta) up to 4 weeks Subacute inflammation (i. subacuta) up to 4–6 weeks Chronic inflammation (i. chronica) more than 6 weeks ni c Neutrophil ro Ch Acute Lymphocyte  Classification of the inflammation II. Based on the reactivity of organism: Normoergic Hyperergic [increased response] Hypoergic [diminished response] Positive vaccines, anti-inflammatory drugs Negative cachexia, old age Anergic  Classification of the inflammation The importance of recognizing these morphologic patterns is that they are often associated with different etiology and clinical situations III. Based on the character of predominant component: SOURCE OF INFLAMMATION ALTERATIVE EXUDATIVE PROLIFERATIVE (i. alterativa) (i. exudativa) (i. proliferativa)  Alterative inflammation Domination of parenchymal cell necrosis of the organ / injury of tissue Acute hepatitis Acute pancreatitis ACUTE ANTERIOR POLIOMYELITIS – HEINE-MEDINA DISEASE  Exudative inflammation Inflammations whose histologic findings include exudation of blood serum and extravasation of blood cells into the inflamed area May be classified as follows according to the principal components of the exudate: Serous Catarrhal mucus, serous, purulent, hemorrhagic Fibrinous croupous and diphtheritic Purulent abscess, phlegmon and empyema Hemorrhagic Putrefactive  Serous exudative inflammation Exudative inflammation with fluid transudates containing small number of cells reflecting increased vascular permeability Biologic purpose: Immediate dilution of the harmful agent at the site of inflammation Etiologic factors: — hypersensitivity reactions — bacterial and viral tissue injury — physical and chemical tissue injury Examples: Serous fluid can also accumulate elsewhere (burn blisters in skin) Initial transitory stage preceding other forms of inflammation Inflammation of serous membranes [pleura, pericardium, peritoneum, and joints (effusions)] Organ inflammation such as serous hepatitis, nephritis, myocarditis, encephalitis Vesicular skin infections Morphology: Erythema and swelling are present with sparse leukocytic infiltrate Serous exudative inflammation 1. 2. 3. 1. TRANSUDATE 2. EXUDATE (SEROUS) 3. EXUDATE (HEMORRHAGIC) SEROUS PLEURITIS Differential Transudate Transparent liquid Exudate (serous) Slightly not quiet characteris Origin: congestion clear liquid tic Up to 3% protein Origin: inflammatory 3-5% protein Isolated mesothelial cells, accidental single A small number of leukocytes and leukocytes erythrocytes desquamated epithelium, mesothelium Serous exudative inflammation  Catarrhal exudative inflammation Exudative inflammation occurring exclusively on the mucous membranes of the respiratory and gastrointestinal tracts and producing a watery exudate of serum and mucus Subtypes: Mucus (most frequent), serous, purulent, hemorrhagic Etiologic factors: — hypersensitivity reactions — bacterial and viral tissue injury — physical and chemical tissue injury Examples: Acute rhinitis (common cold) Acute catarrhal bronchitis Enteritis Morphology: The mucosa and submucosa appear reddened and swollen, with a slight degree of lymphocytic infiltration  Catarrhal exudative inflammation CATARRHAL ASTHM BRONCHITIS  Fibrinous exudative inflammation Exudative inflammation with exudation of fibrinogen containing serum that polymerizes to fibrin outside the blood vessels fibrinolysis resolution organization fibrosis scar, adhesions Biologic purpose: Immediate temporary barrier against additional effects of inflammation Etiologic factors: — Infectious toxic tissue injury [Caused by Corinebacterium diphtheriae, Pneumococcus, Fridlander's bacillus, Frencel's diplococcus, Streptococcus and Mycobacterium tuberculosis] — Tissue injury from physical trauma — Chemical and toxic tissue injury — Excretion of toxic metabolites (uremic toxins) Surface — Ischemic tissue injury Fibrinous pericarditis or pleuritis Fibrinous Inflammation Intestinal Pseudomembranous (Epithelial damage → erosion) Fibrinous Parenchymal Inflammation Enteritis caused by antibiotic Diphtheria larynx Fibrinous Serosal Inflammation Incrustation(Muscle membrane damage → ulcer) Fibrinous Mucosal Inflammation Typhoid bowel  Fibrinous exudative inflammation FIBRINOUS FIBRINOUS COR VILLOSUM – PERICARDITIS PERICARDITIS HAIRY HEART (MICROSCOPY)  Purulent exudative inflammation Inflammation with exudate consisting primarily of died neutrophils and cellular debris (detritus) Biologic purpose: Damaged tissue is dissolved along with the pathogen Etiologic factors – pyogenic bacteria: Caused by Staphylococcus sp., Streptococcus sp., Gonococcus sp, Meningococcuss sp. and Frenkel’s diplococcus Types: Pyorrhea Empyema Surface Phlegmon Pyorrhea (mucous membranes [UT]) Abscess Empyema – accumulation of pus in preformed cavities (pleura, gallbladder) Interstitial Phlegmon – diffuse Abscess acute – border – surrounding tissue chronic – border – pyogenic membrane pseudoabscess – pus in lumen of hollow organ Purulent exudative inflammation  Hemorrhagic exudative inflammation Exudative inflammation involving microvascular injury with massive microvascular bleeding, producing an exudate with a high erythrocyte content Biologic purpose: Exudative inflammation due to severe vascular injury Morphology: The inflamed area is usually necrotic and filled with blood Etiologic factors: — bacterial exotoxins and endotoxins — viral cytopathic effect on endothelium — proteolytic tissue destruction — cytotoxic injury in hypersensitivity type III Examples: Plague Influenzal Pneumonia Disorders Associated with Enterohemorrhagic E. coli Anthrax Viral Hemorrhagic Fever Acute Pancreatitis  Putrefactive exudative inflammation Exudative inflammation with putrid smell Etiologic factors: Putrefactive anaerobic bacteria: Clostridium perfringens Morphology: Massive necrosis without demarcation Clinical course: Severe intoxication, sepsis, death  Proliferative inflammation Acute Acute proliferative glomerulonephritis Chronic Cirrhosis Granulomatous Tissue rich in macrophages, plasmatic cells, fibroblasts Tuberculosis Sarcoidosis Distinctive chronic inflammation type Cell mediated immune reaction (delayed) Aggregates of activated macrophages epithelioid cell multinucleated giant cells Lymphocytic rim NO agent elimination but walling off Positive significance of inflammation Development of necrosis of tissue during alteration promote stopping of blood stream and result in limitation of infection spreading dilution of toxins proteins absorb the toxins Exudation: phagocytosis limitation of toxins matters and mediators spreading in an organism Proliferation of organ or tissue, recover a structure and function Negative significance of inflammation Alteration in the injury → dysfunction of organs Exudate → results in compression of arterial, venous and lymphatic vessels → hypoxia Fibroplasia → results in the organ dysfunction  Total recovery Change of inflammation nature Consequenc Acute → Hyperacute → Chronic es of → Regression inflammatio Neoplasia (NPL) n Colitis ulcerous Type B and C hepatitis Permanent damage of organ structure and function Organ failure Death  Spread of inflammation to other organs through blood and lymph Systemic inflammation Complicatio sepsis ns of SIRS (Systemic inflammatory response syndrome in acute pancreatitis) inflammati cytokinemia → sequestration of WBCs (kidney, lung, liver) on Immunological complications vasculitis glomerulonephritis Metabolic disorders (cachexia, amyloidosis) Osteoporosis (kinins, TNF-α) Anemia (iron deficiency) Reference Kumar V, Abbas A, Fausto N, Aster J. Robbins and Cotran Pathologic Basis of Disease, W.B. Saunders, 9th Edition, 2015 Mitchell R, Kumar V, Abbas A, Fausto N, Aster J. Pocket Companion to Robbins and Cotran Pathologic Basis of Disease, W.B. Saunders, 8th Edition, 2012 Porth CM, Gaspard KJ. Essentials of Pathophysiology: Concepts of Altered Health States, Lippincott Williams and Wilkins, 2003 Copstead Lee-Ellen C. Pathophysiology, Elsevier Inc, 2010 Porth CM, Matfin G. Pathophysiology, Concepts of Altered Health States, New York, Milwaukee, 2009 Silbernagl S, Lang F. Color Atlas of Pathophysiology, Thieme, Stuttgart, New York, 2000  103 Thank You For Being a Fabulous Audience!